16alpha-alkoxy-6-dehydrocortical hormones



United States Patent "ice,

3,141,029 16oc-ALKOXY-6-DEHYDROCORTICAL HORMONES Howard J. Ringold and Albert Bowers, Mexico City, Meiico, assignors, by mesne assignments, to Syntex Corporation, a'corporation of Panama No Drawing. Filed July 29, 1959,, Ser. No. 830,211

Claims priority, application Mexico July 29, 1958 Claims. (Cl. 260397.45)

This invention relates to certain new cyclopentanoperhydrophenanthrene derivatives and to a process for producing the same.

More particularly, it relates to novel 16a-alkoxycortical hormones, and more specifically to the 1 6a-alkoxy(methoxy, ethoxy, propoXy) derivatives of cortisone, hydrocortisone, prednisone and prednisolone, to their 9nhalo(fluoro, chloro or bromo) analogs and to the 21- esters of the aforementioned compounds, which have an additional double bond between C-6 and C-7 and are free from or have substituents at one or both of the positions C-2 and 0-6, which substituents are at the a-position in the compounds saturated between C-1 and C-2 or between C6 and C-7, respectivelyi substituents at C-2 can be the methyl or ethyl group, and substituents at position C-6 can be the methyl group or a fluorine, chlorine or bromine atom.

The new compounds, object of the present invention,

' are cortical hormones having a marked anti-inflammatory,

thymolytic, anti-androgenic and anti-estrogenic activity.

These compounds are characterized by the following general formula:

OHZOR ---Alkoxy XMN 011 =0 or H and Z is selected from the group consisting of a single 'bond between C-1 and C-2 and a double bond between -C1 and C-2, and Z is selected from the group consisting of a single bond between C-6 and C-7 and a double bond between C- 6 and 0-7.

The process for producing these new compounds ac- 3,141,029 Patented July 14, 1964 cording to our invention can be illustrated by the follow ing equation:

OH OAcyl l I I ...0H

CH OR In the above equation R, X, X, X", Y, Z and Z represent the same groups as described further above; acyl represents a radical of any hydrocarbon carboxylic acid having up to 1-2 carbon atoms per molecule, which acid may be saturated or unsaturated, of straight or branched chain, cyclic or mixed cyclic-aliphatic, and may be unsubstituted or substituted by methoxy, halogen or other groups. Alkoxy represents the lower radicals such as methoxy, ethoxy, propoxy and the like up to 5 carbon atoms per radical.

The starting compounds I are available from difi'erent sources. Thus the compound in which Z is a single bond and X' is hydrogen is manufactured by Lederle Co. and is commercially available under the name of Triamcinolone, :having the formula:

OH OAcyI 1 s --OH XII ID: 2: =6, z =c=o and in which Xis hydrogen, M is chlorine or bromine and Z and Z single or a double bond, and which will be designated as IA, IB, IC and ID hereinafter, can be achieved by the processes described in the co-pending patent applications Serial Nos. 670,366 and 670,368, both filed on July 8, 1957, and 740,550, filed June 9, 1958, now US. Patent No. 2,934,546, and assigned to the same assignee as the present application and by the subsequent no M acetic acid Dry H01 microbiological introduction of a free hydroxyl group at C-16 in tat-configuration as described in the co-pending application Serial No. 830,212, filed July 29, 1959, now abandoned.

The production of these new compounds can be illustrated by the following Reaction Diagram I:

REACTION DIAGRAM I GHzOAc Perphthallc acid Hydrogen chloride (or hydrogen bromide) in acetic acid CH OAo CHzOAe i=0 i=0 fil jonc -"OAc Oxidation Ohromic acid CH OAc (5:0 1. Selenium X dioxide 0 Acetic anhydrido pyridine GHgOAe Oxidation chromic acid XM 413. I

\ Mierobwfimxylation Dehydrogenatio n X CHgOAO it)? m In the above equations Ac represents the acetate radical or any other corresponding lower fatty acid ester radical, M represents chlorine or bromine, and X and Z represent the same groups as heretofore set forth. In practising the process above set forth, the l7a,21-diacetate or other lower fatty acid ester of A -pregnene-3fi,17a,21- triol after oxidation with monoperphthalic acid affords the corresponding 17,21-diacetate or other ester of 5a,'6aepoxido-pregnane-hfi,17a,21-trio1-20-one. This epoxide is then subjected to halogenation with dry hydrogen chloride or bromide in acetic acid to obtain the corresponding 17,21-diacetate of 6fl-chloro(or bromo) -pregnane- 313,5a,1704,21-t6t10l-20-O116. The 3fi-hydroxyl group is then oxidized to a keto group by reaction With concentrated chromic acid. When, for instance, the 17,2l-diacetate of 6p-chloro-pregnane-5a,17a,21-triol-3,20-dione is dehydrated at C-5 by reaction with dry hydrogen chloride in acetic acid solution there is formed the diacetate, or other lower fatty acid ester. If another ester has been used in the reaction, of 6a-chloro-A -pregnene-l.7a,21- dio1-3,20'-dione. This compound may be converted to the corresponding l-dehydro-S derivative by treatment S802 or chloranil and n-amyl alcohol I with selenium dioxide. After saponification of the diacetates (with or without double bond in 1, 2 position) an 11 fi-hydroxy group can be introduced by incubation with adrenal tissue under the conditions set forth in US. Patent No. 2,671,752, granted March 9, 1954, to Alejandro Zafiaroni, whereby 6a-chloro-hydrocortisone and 60cchloro-prednisolone are formed. llp-hydroxyl derivatives thus prepared may then be oxidized with chromic acid to form the corresponding cortisone or prednisone type derivatives, namely, 6a-chloro(or bromo)-cortisone and 6u-chloro(or bromo)-prednisone.

The respective 6-bromo-derivatives are obtained in the same manner.

The above 6oc-chloro-A -pregnene-l7a,21-dio1-3,11,20- trione ZI-acetate or '6a-ch1or0-A -pregnadiene-17u,21- diol-3,11, 20-trione, or the corresponding compounds of the above formulas in which Y is ,G-hydroxyl, are then saponified and the free alcohols microbiologically hydroxylated at C-18, by incubation with Streptomyces roseochromogenus. After conventional re-esterification, for instance with acetic acid, the resulting starting compounds IA and IB are thus: =6ot-chloro-(or bromo)-A pregene-16a,17a,2l-triol-3,11,20-trione ZI-acetate,

6u-chloro (or bromo)/A -pregnene-11fl,16a,17a,21-tetro1-3,20-dione ZI-acetate,

6a-chloro( or bromo) -A -pregnadien-16a,17a,2 l-triol- 3,11,20-dione ZI-acetate, or

6a-chloro(or bromo)-A -pregnadien-l 1 [3,16a, 17a,-21- tetro1-3,20-dione 21-acetate or other 21-esters.

Of these intermediates, those having the general Formula IA can be further converted to the above-mentioned starting compounds IB, and to IC and ID by the further steps shown in the above Reaction Diagram I as described hereinafter:

The preferred intermediate IA is one where R represents the acetate radical. Refluxing with selenium dioxide preferably in mixture with t-butanol in the presence of pyridine gave the corresponding diene compounds (1B), and refluxing these dienes with chloranil in n-arnyl alcohol or Xylene gave the corresponding .21-acetate of A -trienes (ID). These last compounds were also obtained directly from the A starting materials by refluxing with chloranil in n-amyl alcohol. Refluxing the A starting compounds with chloranil in xylene however, produced the A -derivatives (IC) indicated which could be transformed to the A -derivatives (ID) by a second treatment with chloranil in n-amyl alcohol or by REACTION DIAGRAM II C Hz 0 R Dry hydrogen chloride acetic acid Microbiological hydroxy (IJHzOR 0:0

Ohloranil and xylene CH OR Ohloranil amyl alcohol dehydrogcnation With SEC:

lSeO; 0r chloranil and n-amyl alcohol CHzOR refluxing with selenium dioxide. As may be understood, other esters of the type previously set forth may be used instead of the acetates and the A A and A ester compounds prepared may be conventionally saponified and reesterified.

Another possible process of producing the above-mentioned starting compounds in which M is chlorine or bromine and X and X" is hydrogen is described in the co-pending applications Serial Nos. 670,366 and 670,368, both filed on July 8, 1957, as well as Serial No. 830,212, filed July 29, 1959, now abandoned, and comprises the steps illustrated in the following Reaction Diagram II:

CHQOR Mlcrobiologi cal ydroxylation CHzOR (i=0 (5:0 i. OH OH Y Y?" I X l X ()Hloranil alcohol or xylene Referring to the equation, for the first step, when the 11 position is occupied by a keto group, the 2l-acetate of 3-ethylene dioXy-5a6a-oxido-pregnan-l7a21-diol-11,20- dione (prepared from cortisone acetate as set forth by Sondheimer, Mancera and Rosenkranz, J.A.C.S., 76, 5020 (1954) is suspended in glacial acetic acid and a slow stream of dry hydrogen chloride is passed into the suspension. Desirably, the temperature is kept below room temperature and preferably close to the freezing point of glacial acetic acid or below 15 C. The hydrogen chloride is passed into the reaction mixture for a period of time of the order of 2 hours and the resulting solution is then poured into ice water. The product after usual extraction with an organic solvent and purification is the ZI-acetate of 6a-chloro-A -pregnen-17a,21- diol-3,11,20-trione. Although the acetate was found desirable as the starting material it is obvious that other esters of the character described may be used as starting materials with the consequent production of corresponding esters of the product. These other ester starting materials may be prepared from the corresponding esters of cortisone.

The 21-esters of 6a-chloro-A -pregnen-17a,21-dio1-3,11, 20-trione preferably the lower fatty acid esters such as the acetate upon heating in an organic solvent (a preferred medium was t-butanol having a catalytic amount of pyridine) with selenium dioxide for a prolonged period of time of the order of 70 hours and purification gave the corresponding 21-ester of 6u-chloro-A -pregnadien-17a, 21-diol-3,11,20-trione. Here again saponification gave the free compounds and esterification other hydrocarbon carboxylic esters of 2 to 12 carbon atoms.

The further microbiological hydroxylation of the two last mentioned compounds to the corresponding 16a-hydroxy derivatives and the conversion of intermediate IA, 2. starting material for the process of the present invention, to starting materials 1B, 1C, and ID is identical with the process steps described in connection with Reaction Diagram I.

Starting materials IA", 1B", IC" and 1])" which are suitable for use in the process described in the present invention and have the above-mentioned general Formula I in which the substituent in 6a-position is hydrogen, methyl, or fluorine, can be produced by the process described in the co-pending application Serial No. 762,232, filed September 22, 1958, and assigned to the same assignee as the present application. This process comprises the steps shown in the reaction diagram below:

CHzO R O CHzOH 1 o o l XII X Ethylene glycol X W O: Esterification O i M M l Dehydration 011 011 011 0 R \0 \O HO o= X l X X NW X /wv Reducing O F agent I:

O E M M l Hydrolysis l Hydrolysis GH2OH 0112011 XII X NW l X NW 0: 0-

Osmium tetroxide C H O R C H; O R i I o O H 0 H OH Y O H XII XI! X I o hloranil X l xylene I I! II I E M M Dehydration Chloranil Selenium dioxide (selenium or chloranil and dioxide) n-amyl n-arnyl alcohol alcohol CHzO R CHzO R I =0 1 =0 n u s O H Y 0 H Y 0H XII XII fij Chloranil 4/13 BI! I n l M M In the above reaction diagram X, X", Y and R represent the same groups as heretofore set forth. M represents either hydrogen, methyl or fluorine.

In practicing the process outlined in this second diagram, a known compound which is either cortisone, a 9u-halogenated cortisone in which the halogen can be fluorine, chlorine or bromine, 6a-methyl cortisone or one of the aforesaid 9a-halogenated cortisone derivatives having the methyl group as a substituent at 0-6, or 6oc-fil101'0- cortisone, or one of the aforesaid 9a-halogenated cortisone derivatives having the methyl group as a substituent at C-6, is conventionally refluxed with ethylene glycol in the presence of benzene and p-toluenesulfonic acid to form the corresponding 3,20-bis-eycloethyleneketals thereof. The bis-ketals were then conventionally acylated at 0-21 to form conventional esters as indicated in the equation. The esters were then reacted with thionyl chloride in pyridine solution to form the corresponding 21-acylate of unsubstituted or 6-substituted 3,20-bisethylenedioxy-A -pregnadien-Zl-ol-ll-one, or its 90cfluoro or 9a-chloro analogue. The acyl group was then saponified by reaction with an alkali metal hydroxide under mild conditions and the ketal groups hydrolyzed with acid to prepare, for instance, when M is fluorine, 6oc-fl1101O-, 6a-fluoro-9a-ch1oroor 6a,9oc-diflllOrO-A pregnadien-21-ol-3,11,20-trione. The corresponding compounds having an 11,8-hydroxy group were prepared by reducing the ll-keto group of the last mentioned 3,20-bisethylenedioxy derivatives with lithium aluminum hydride. Reaction of A -compounds having either an ll-keto or 11 B-hydroxy group with osmium tetroxide under the conditions described by Bernstein et al. (J .A.C.S. 78, 1909 (1956)) yielded the intermediates of the general formula IA", namely, if M is fluorine, 6a-fiuoro-A -pregnen-l6a, 17a,21-triol-3,l1,20-trione, 6a,9a-difluoro-A -pregnen-l6a, 17a,2l -triol 3,11,20-trione and 6a-fluoro-9u-chloro-A pregnen-16a,l7a,2l-triol-3,l 1,20-trione as well as the 115- hydroxy derivatives namely 6a-fluoro-, 60:,9a-difil1010- and 6a fluoro 9u-ch1oro-A -pregnen-1l,8,l6u,l7u,2l-tetrol- 3,20-dione or the 21-esters thereof. If M is the methyl group, there are obtained the 6u-methy1 corresponding compounds.

The reaction of all of these compounds with selenium dioxide in t-butanol yielded the corresponding A -dienes IB". Preferably this reaction was effected with the compounds in the form of their 2l-monoesters followed by subsequent conventional saponification to form the free dienes.

All of the above compounds upon conventional esterification yield the corresponding 21-mono esters of the type previously set forth, using only a slight excess of acid anhydride.

The unsubstituted or 6-substituted starting compounds IC' and ID of the present invention are obtained from intermediates IA" or IE" by reactions with chloranil as described above in connection with the first reaction diagram for the 6-chlorinated compound.

The l6-hydroxy derivatives constituting the starting materials of the present invention can also be obtained by microbiological hydroxylation of the corresponding known 16-unsubstituted derivatives of cortisone, hydrocortisone, prednisone and prednisolone. By incubation of one of the aforesaid 16-unsubstituted compounds with Streptomyces roseochromogenus, a hydroxyl group is introduced in position in these compounds.

According to the process of our present invention, the novel compounds of the invention are obtained from a 21- ester of the respective l6a-hydroxy compound (I) by reaction with a diazoalkyl (diazomethane, dioazoethane or diazopropane) in the presence of a catalyst such as boron trifluoride etherate or fluoro-boric acid HBF Preferably we employed fiuoroboric acid and conducted the reaction with an excess of the diazoalkyl, at room temperature and in mixture with methylene chloride and ether, although the reaction can be carried out in other solvents such as ether, acetone or mixtures of both. The use of fiuoroboric acid has been described by Caserio, Roberts, Neeman and Johnson, I. Am. Chem. Soc., 80, 2584 (1958).

Thus we obtained the corresponding 21-esters of the respective 16a-alkoxy compounds II in which R is acyl. The ester group was then hydrolyzed, preferably by treatment with dilute methanolic solution of sodium methoxide or potassium hydroxide, at low temperature and 13 under an atmosphere of nitrogen, to produce the respective 21-hydroxy compounds II in which R is H. The hydroxyl group at C2l was reesterified by reaction with the anhydride of a carboxylic acid in pyridine solution.

The ester groups at C-2l of I and II may be formed with the radical of any of the above-mentioned carboxylic acids. The esters of II are obtained either starting from the corresponding 21-ester of I or by using the anhydride of the corresponding acid in the step of reesterification. We prepared, among others, the following: 21-esters of II: acetates, propionates, t-butyrates, hemisuccinates, enanthates, caproates, benzoates, trimethylacetates, phenoxyacetates, cyclopentylpropionates, phenylpropionates and ,B-chloropropionates.

To name a few particular examples of practicing the process of the invention, use of the 21-esters of 16a-hydroxy-prednisone or of 16ot-l1YdIOXY-P1'EGI11SO10116, with or without the respective substitutes at C-Za, C6a and C9a as starting materials affords the corresponding 21- esters of the respective 16u-alkoxy-prednisones and 16aalkoxy-prednisolones, with or without the corresponding substituents at C2, C6a, and C9a.

Use of the 21-esters of A -pregnadiene-l6a,17ot,21- triol-3,1l,20-trione or of A -pregnadiene-l1l3,16ot,17a, 21-tetrol-3,20-dione, with or without the respective substituents at CZa, C-6 and C9OL as starting materials leads to the production of the corresponding 2l-esters of the respective 16cc alkoxy-A -pregnadiene-17a,21-diol-3,11, 20 -triones or 16a-alkoxy-M -pregnadiene-11,8,17a,21- triol-3,20-diones, with or without the corresponding substituents at C2a, C6 and C9a.

And if the 21-esters of A -pregnatriene-l6u,l7u,21- triol-3,11,20-trione and of A -pregnatriene-l1,6,16oc,17a, 2l-tetrol-3,20-dione, with or without the respective substituents at C2, C6 and C9a are used as starting materials, there are obtained the corresponding 21-esters of the respective l6a-alkoxy-A -pregnatriene-17a,21-diol- 3,11,20-triones and 16ot-alkoxy-A -pregnatriene -11,B, 17a,21-triol3,20-diones, with or Without the corresponding substituents at C2, C6 and C9a.

The invention shall now be illustrated by a number of more specific preparations and examples which are, however, not intended as limitative of the scope of the invention.

PREPARATION I 1.5 mols of perphthalic acid in ether was added to a solution of 5 g. of the 17,21-diacetate of A -pregnene- 3fl,l7ot,21-triol-20one in 100 cc. of chloroform and the mixture was kept for 20 hours at room temperature. After dilution with water, the organic layer was separated, washed with water, sodium bicarbonate solution and water to neutral, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Crystallization of the residue from acetonehexane aiforded the 17,21-diacetate of 5a,6u-oxido-pregnane-3B,17a,21-trio1-20-one, M.P. 198200 C., [oc] 54 (chloroform). A slow stream of dry hydrogen chloride was bubbled for two hours into a solution 5 g. of the preceding epoxide in 200 cc. of chloroform while the temperature was maintained below 10 C., the mixture was diluted with water and the chloroform layer was separated and washed with water, until neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane furnished the Nail-diacetate of 6fl-chloro-pregnane-3B, 5oc,17u,2l-ttl'Ol-200n6.

A solution of 3 g. of this tetrolone in 150 cc. of acetone was treated with an 8-normal solution of chromic acid prepared by mixing 1.6 g. of chromium trioxide with concentrated sulfuric acid and water. This oxidizing reagent was added dropwise to the stirred solution while the temperature was maintained below in the course of 2 minutes. The stirring was continued for minutes further at 0 C. and then the solution was diluted with water and extracted with ether. The ether extract was 14 washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to produce the 17,21-diacetate of 6,8- chlQroregnane-Sa, 17a,21-t1l0l-3,20-dl0116.

2 g. of the 17,21-diacetate of 6 8-chloro-pregnane-5m, 17a,21-triol-3,20-dione was dissolved in cc. of glacial acetic acid and a slow stream of dry hydrogen chloride was passed into the solution for 2 hours at a temperature around 18 C. The mixture was poured into ice water, the precipitate formed was collected and washed with water, dried and crystallized from acetone-hexane. There was thus produced the diacetate of 6a-chloro-A -pregnene- 17a,21-diol-3,20-dione, ultraviolet absorption A max, 236 III/1., log 6 4.22. When the starting material was other 17,21-diesters of A -pregnen-3fi,17a,21-triol-20-one, the corresponding 17,2l-diesters of 6u-chloro S were obtained. These were the dipropionate, dicaproate and dibenzoate.

1 g. of the 17,21-diacetate of 6a-chloro-S obtained as has been described above, was suspended in 10 cc. of 1% methanolic potassium hydroxide previously cooled to 0 C. The mixture was stirred for 2 hours at 0 C., under an atmosphere of nitrogen, neutralized with acetic acid, diluted with water and the precipitate was filtered, washed with water, dried and crystallized from acetonehexane. There Was thus obtained the free 6u-chloro- M-pregnene-17a,21-dio1-3,20-dione, i.e., 6a-chloro-S.

A mixture of 5 g. of the diacetate of 6oc-Chl01O-A pregnene-l7a,2l-diol-3,20-dione, 250 cc. of anhydrous t-butanol, 1.5 g. of selenium dioxide and 0.5 cc. of pyridine was refluxed for 70 hours under an atmosphere of nitrogen, cooled, diluted with ethyl acetate and filtered through celite; the filter Was washed with hot ethyl acetate and the combined filtrate and washings was evaporated to dryness under reduced pressure. The residue was triturated with water, the precipitate was collected, dried and purified by chromatography over 250 g. of washed alumina. Elution of the column with benzeneether and ether and evaporation to dryness of the fractions afforded crystalline products which were combined and recrystallized from acetone-hexane, thus producing the diacetate of 6a-chloro-A -pregnadiene-17a,21-diol- 3,20-dione. Other esters of hydrocarbon carboxylic acids of 2 to 12 carbon atoms were also thus prepared such as the dipropionate and dicaproate.

A suspension of 2 g. of the diacetate of 606-(1111010- A -pregnadiene-17a,21-diol-3,20-dione in 20 cc. of absolute methanol was mixed with a solution of sodium methoxide in methanol prepared by dissolving mg. of sodium in 5 cc. of absolute methanol; the addition was carried out With stirring under an atmosphere of nitrogen at 0 C. The stirring was continued under nitrogen for 2 hours at 0 C., and then the mixture was poured into 50 cc. of water containing 1 cc. of acetic acid, the precipitate was filtered, washed with water, dried and recrystallized from acetone-hexane, thus producing the free 6a-chloro-A -pregnadiene-17a,2l-diol- 3,20-dione.

The following solutions A, B and C were prepared using distilled water as solvent: solution A was prepared by mixing 425 cc. of a 1.742% dipotassium hydrogen phosphate solution (K HPO with 75 cc. of 1.38% monosodium dihydrogen phosphate; solution B was prepared by diluting a mixture of 1 1t. of 4.5% sodium chloride solution, 40 cc. of a 5.75% potassium chloride solution and 10 cc. of a 19.1% magnesium sulfate, to a volume of 5 lt.; solution C was prepared by dissolving 20.9 g. of fumaric acid and 14.4 g. of sodium hydroxide in 1 1t. of water and diluting the solution to 1.2 It. Then 475 cc. of solution A, 4.32 It. of solution B and 1.2 It. of solution C were mixed.

The fat was removed from the adrenal glands obtained from recently slaughtered bovine and the glands were ground in a meat grinder until an homogeneous mass was obtained; 3 kg. of this mass was then added to 6 1t.

15 of the mixture of solutions A, B and C, obtained as described above, and the mixture was vigorously stirred.

There was then added 3 g. of 60tCI1lOlO-A -pIGgTl8IlC- 17a,21-diole-3,20-dione in 16 cc. of propylene glycol and the mixture was stirred again at a temperature of 28 37 C. for 3 hours. 40 lt. of acetone was then added and the stirring was continued for one hour further at room temperature.

The solid was removed by filtration and washed twice with 10 lt. fractions of acetone; the washings were combined with the filtrate and concentrated under reduced pressure below 30 C., to a volume of approximately 5 it. The aqueous residue was washed three times with 4 lt. portions of hexane and the hexane was discarded. The aqueous residue was then extracted with 2 portions of 3 lt. of methylene dichloride, the extract was washed with water, dried over anhydrous sodium sulfate, and concentrated to a volume of approximately 300 cc., under vacuum and below room temperature.

The concentrated solution was allowed to pass through a column prepared with a mixture of 90 g. of silica and 90 g. of celite. The column was washed with 3 It. of methylene dichloride and then with a mixture of 900 cc. of methylene dichloride and 100 of acetone. The product was then eluted with mixtures of methylene dichloride and acetone (80:20 and 70:30). The solvents from these elutions was evaporated and the residue crystallized from ethyl acetate. There was thus obtained 6a-chlorohydrocortisone.

1 g. of 6a-chloro-hydrocortisone was mixed with cc. of pyridine and 1 cc. of acetic anhydride and allowed to stand overnight. It was then poured into ice water, stirred for half an hour at room temperature, and the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane, thus giving the 21- acetate of 6a-chloro-hydrocortisone.

A stirred solution of 500 mg. of the 2l-acetate of 6mchloro-hydrocortisone in 30 cc. of acetic acid was slowly treated with a solution of 130 mg. of chromic acid in 1 cc. of water and 8 cc. of acetic acid and the mixture was kept at room temperature for 2 hours. After pouring into water, the precipitate was filtered, washed with water, dried and recrystallized from acetone-hexane to yield the 21-acetate of 6a-chloro-cortisone.

There was prepared a sporulated culture of Streptomyces rosco-chromogenus Rutgers 3689 in an inclined medium of agar containing 1% of glucose and 1% of yeast extract. With 1 cc. of a suspension of this culture there was inoculated each of a series of 250 cc. Erlenmeyer flasks containing 50 cc. of a liquid aqueous medium containing 2% of peptone and 5% of corn syrup, and the mixtures were then incubated in a stirring machine at 28 C., under aeration for 24-48 hours. There was thus obtained a vegetating growing culture of Strepton'zyces roseoclzromogenus which was used for the subsequent incubation with the steroid.

To the vegetating growing culture of Streptomyces roseochromogenus obtained as described in the above preparation there was added the free 6ot-chloro-cortisone in the proportion of 10 mg. of the latter for every 50 cc. of culture, which was then stirred at 28 C. for 48 to 72 hours, under aeration. The mixture was then extracted several times with methylene dichloride and the extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure.

The residue was purified by chromatography on silical gel. After re-esterification with acetic acid anhydride in pyridine there was obtained the 21-acetate of 6tx-chloro- 16a-hydroxy-cortisone, A max: 234 m (log 6 4.16) (IA).

In the same manner, the 21-acetate of 6u-chloro-hydrocortisone was saponified and the free alcohol hydroxylated at C-16 and, after re-esterification, there was obtained the 21-acetate of 6a-chloro-16a-hydroxy-hydrocortisone (IA).

1 6 PREPARATION II 1.5 g. of the 21-acetate of 6a-chloro-A -pregnen-16a, 17a,21-triol-3,11,20-trione (IA) obtained as described above in this same preparation, was mixed with 75 cc. of anhydrous t-butanol, 450 mg. of selenium dioxide and 0.2 cc. of pyridine and the mixture was boiled under reflux for 72 hours under an atmosphere of nitrogen. The cooled mixture was diluted with ethyl acetate, filtered through celite and the residue was washed with hot ethyl acetate. The filtrate and washings were combined and evaporated to dryness under reduced pressure. The residue was triturated with water and the precipitate was collected, washed, dried and purified by chromatography on neutral alumina. There was thus obtained the 2l-acetate of 60a chloro A -pregnadien-16u,17a,21-triol-3,1 1,20- trione (IB).

PREPARATION III A mixture of 1.5 g. of the above A -con1pound (IA), 2 g. of chroranil and 30 cc. of n-amyl alcohol was refluxed for 16 hours, cooled and diluted with 60 cc. of ether. The solution was successively washed with water, 5% sodium carbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography on ethyl acetate-washed alumina yielded the pure ZI-acetate of 6-chloro-A -pregnatrien-16a,17a,21-triol-3,11,20-trione (ID).

PREPARATION IV A mixture of 5 g. of the 21-acetate of 6ot-chloro-A pregnen-16a,17a,21-triol-3,11,20-trione, obtained by the method of Preparation I, 9 g. of chloranil and 250 cc. of tertiary butyl alcohol was refluxed for 12 hours, cooled and diluted with ether. The solution was washed with water, 5% sodium carbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was purified by chromatography on neutral alumina to produce the Zl-acetate of 6- chloro A pregnadien-16u,17a,21-triol-3,11,20-trione (IC).

1 g. of the above compound (IC) was refluxed with 300 mg. of selenium dioxide, 50 cc. of anhydrous t-butanol and 0.2 cc. of pyridine for 70 hours under an atmosphere of nitrogen. The product was then worked up by the procedure described in Preparation II. There was thus obtained the 2l-acetate of 6-chloro-A -pregnatrien-16a, 17a,21-triol-3,11,20-trione (ID), identical to the compound (ID) obtained before.

Alternatively, 1 g. of the above A -diene (IC) was refluxed with 1.5 g. of chloranil and 20 cc. of n-amyl alcohol and then the reaction product was worked up as described above in. this preparation, thus producing the 2l-acetate of 6-chloro-A -pregnatrien-16a,l7u,21-triol- 3,11,20-trione (ID), identical to the one obtained hereinbefore. In another preparation the n-amyl alcohol was substituted by xylene, with the same final result.

PREPARATION V By an analogous method to that previously described in Preparation I but starting from 6a-chloro-A -pregnadiene-17a,2l-diol-3,20-dione, there are obtained the 21- acetate of 6u-chloro-prednisolone, as well as the 21-acetate of 6a-chloro-prednisone, respectively. The latter compound is then further treated as described under Preparation I by microbiologically introducing the 16a-hydroxy group and then is directly obtained the above-mentioned starting compound IB.

PREPARATION VI The procedure of Preparation I is repeated but hydrogen bromide is used instead of hydrogen chloride as indicated in the first reaction diagram above.

There are obtained the 21 monoacetates of 6a-bromo- A -pregnene-16ot,l7ot,2l-triol-3,l1,20-trione and the corresponding A -analog.

1 7 PREPARATION VII The procedure of Preparation I is repeated with hydrogen bromide instead of hydrogen chloride, and there are obtained the 21 acetate of 6u-bromo-A -pregnene-l1B, 16a,17a,2l-t6tr01 3,20-dione and the corresponding A analog.

PREPARATION VIII A slow stream of dry hydrogen chloride was passed for 2 hours through a mixture of 2 g. of the 21-acetate of 3,20- bis ethylenedioxy 5,6 oxido pregnan-115,l7a,21-triol and 100 cc. of glacial acetic acid, maintaining the temperature of the mixture below 15 C. The resulting clear solution was poured into ice water and extracted with methylene dichloride. The extract was washed with watensodium carbonate'solution and water, dried over anhydrous sodium sulfate and evaporated to dryness. Two crystallizations of-the residue from acetone-hexane afforded the 2l-acetate of 6a-chloro-A -pregnene-11,8,17a, 21-triol-3,20-dione.

A mixture of 500 mg. of the above compound, 25 cc. of anhydrous t-butanol, -l50 mg. of selenium dioxide and 0.05 cc..of-pyridine was refluxed for 70 hours under an atmosphere of nitrogen. The cooled mixture was diluted with 50cc. of ethyl acetate and filtered through celite, washing well with ethyl acetate. The ethyl acetate solution was evaporated todryness under vacuum and the residue was triturated with water and collected. The dry precipitate was chromatographed in a column with 25 g. of Washed alumina and the crystalline fractions eluted from the column with benzene-ether and ether were combined and crystallized from acetone-hexane, thus yielding the ZI-acetate of 6u-chloro-A -pregnadiene- 11/3,17a,21-triol-3,20-dione.

To a vegetating growing culture of Streptomyces roseo- .chromogenus Rutgers 3689 obtained as described above in Preparation I there .was added 6a-chloro-A -pregnenel1,8,17a,2l-triol-3,20-dione in the proportion of mg. of the latter for-every 50 cc. of culture, which was then stirred at 28 C. for 48 to 72 hours, under aeration. The mixture was then extracted several times with methylene dichloride and the extract was washed with Water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure.

The residue was purified by chromatography on silica gel. After re-esterification of the free alcohol there was obtained the Zl-acetate of 6a-chloro-A -pregnene-115,16,

17u,2l-tetrol-3,20 dione (IA). The conversion of the latter starting compound IA to the other starting compounds IB', ICand ID was carried out followingthe procedure .set forth indeta'il in Preparation I.

PREPARATION IX The microbiologicalintroduction of a hydroxyl group atCl6 position described in Preparation II was repeated with the ZI-acetate of.6a-chloro-A -pregnadiene-l15,

.17a,21-triol-3,20-dione and there was obtained the corresponding l6a-hydroxyl analog (IB). The conversion of the latter'tostarting compound ID is carried out with .chloranil in alcohol or xylene as described under Preparation I.

PREPARATION X from acetone-hexane, thus giving 1.48 g. of the 2l-acetate of 6a-chloro-A -pregnen-17a,21-diol-3,11,20-trione with I8 M.P.190192 C., A max. 233 m;r,log e 4.10, [111 +179 (chloroform).

A suspension of 500 mg. of the latter compound in 25 cc. of anhydrous t-butanol, 150 mg. of selenium dioxide and 0.05 cc. of pyridine was refluxed for 70 hours under an atmosphere of nitrogen. The cooled mixture was diluted with 50 cc. of ethyl acetate and filtered through celite, washing well with ethyl acetate. The ethyl acetate solution was evaporated to dryness under vacuum and the residue was triturated with water and filtered. The dry precipitate was chromatographed in a column with 25 g. of washed alumina and the crystalline fractions eluted with benzene-ether and ether were combined and crystallized from acetone-hexane, thus yielding mg. of the Zl-acetate of 6ot-chloro-A -pregnadiene-17a,21- diol-3,11,20-trione with M.P. 217-219 C., max. 238 my, log a 4.18.

The further treatment of the above two resulting compounds is carried out following the same procedure as described in Preparations I, VIII and IX.

PREPARATION XI A mixture of 6 g. of 6a-fluoro-cortisone, cc. of anhydrous benzene, 48 cc. of ethyleneglycol, distilled over sodium hydroxide, and 0.6 g. of p-toluenesulfonic acid was refluxed for 8 hours with the use of an adapter for the continuous removal of the water formed during the reaction. The cooled mixture was mixed with sodium bicarbonate solution and the organic layer was separated and washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Crystallization of the residue from acetonehexane yielded the 3,20-bis-cycloethyleneketal of 6afiuorocortisone. The pure product was obtained after recrystallization from acetone-hexane.

5 g. of the above crude ketal was dissolved in 30 cc. of pyridine, mixed with 5 cc. of acetic anhydride and kept overnight at room temperature. After pouring into water the product was extracted with methylene dichloride, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue consisted of the 21-acetate of the crude 'ketal of 6a-fluoro-cortisone.

A solution of 5 g. of the 21-acetate bis-ketal of 60L- fiuoro-cortisone (6 fluoro 21 acetoxy-3,20-bis-ethylenedioxyA -pregnen-l7a-ol-1l-one) in 50 cc. of pyridine was cooled to 0 C. and mixed under stirring with 3.0 cc. of thionyl chloride. The stirring was continued for 1 hour at 0 C. and then the mixture was poured into ice water and the product was extracted with methylene dichloride, well washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography, thus furnishing the 'Zl-acetate of 6-fluoro-3,20-bis-ethylenedioxy-A -pregnadien-Zl-ol-l l-one.

5 g. of the above acetate was mixed with 50 cc. of 1% potassium hydroxide in methanol previously cooled to 0 C., and the mixture was stirred at 10 C. under an atmosphere of nitrogen for 1 hour. It was then neutralized with acetic acid and diluted with water. The precipitate was collected, washed with Water, dried and purified by crystallization from acetone-hexane, thus giving the pure 6-fluoro-3,20 bis-ethylenedioxy A -pregnadien 2l-olll-one.

A solution of 4 g. of the above compound in 700 cc. of ethanol was treated with 100 cc. of dilute sulfuric acid (8% by volume), refluxed for 40 minutes, cooled and neutralized with solid sodium bicarbonate; the mixture was concentrated to a small volume underreduced pressure and diluted with water. The precipitate was collected by filtration, washed with water, dried and crystallized from acetone-hexane, thus yielding the pure 6afiuoro-A -pregnadien-2l-ol-3,1 1,20-trione.

A solution of 3 g. of the above compound in 60 cc. of anhydrous benzene and 2.8 cc. of pyridine was mixed with 3 g. of osmium tetroxide and the mixture was allowed to stand in the dark at room temperature for 4 days; the osmic ester was then decomposed by the addition of 150 cc. of water, 60 cc. of benzene, 110 cc. of methanol, 18 g. of sodium bicarbonate, with stirring for 4 hours, 200 cc. of chloroform was then added and the dark precipitate was filtered and washed with 800 cc. of hot chloroform. The organic layer was separated from the combined filtrates which was then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated with acetone, thus producing 6a-fluoro-16a-hydroxy-cortisone in crude form (6ot-fiuoro- A -pregnen-l6a,17u,21-triol-3,11,20-trione) Concentration of the mother liquors afforded an additional crop.

1 g. of 6a-flt1010-l60c-hYdIOXY-CO1'fiSOI16 was dissolved in 10 cc. of pyridine, cooled to C. and treated with approximately 0.3 cc. (1.1 mols) of acetice anhydride and the mixture was kept at 10 C. for 2 hours and then poured into water. The product was extracted with ethyl acetate, washed with dilute hydrochloric acid, sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from ethyl acetate yielded the 21-acetate of 6u-fluoro-l6ot-hydroxy-cortisone (6afluoro A pregnene l6oc,17ct,21 triol 3,11,20 trione 21-acetate).

1.5 g. of the 2l-acetate of 6ot-fiuoro-A -pregnene-16cc, 17a,21-triol-3,11,20-t1ione obtained as described above in this preparation, was mixed with 75 cc. of anhydrous t-butanol, 450 mg. of selenium dioxide and 0.2 cc. of pyridine and the mixture was boiled under reflux for 72 hours under an atmosphere of nitrogen. The cooled mixture was diluted with ethyl acetate, filtered through celite and the residue was washed with hot ethyl acetate. The filtrate and washings were combined and evaporated to dryness under reduced pressure. The residue was triturated with water and the precipitate was collected, washed, dried and purified by chromatography on 25 g. of washed neutral alumina. Elution with mixtures benzene-ether and with ether, followed by crystallization of the combined crystalline fractions afforded the 21-acetate of 6oc-fiuoro-1Ga-hydroxy-prednisone (6a-fiuoro-A -pregnadiene-16a,17ot,21-triol-3,11,20-trione 2 l-acetate).

l g. of this diene was refluxed with 1.5 g. of chloranil and 20 cc. of n-amyl alcohol and then the reaction product was worked up by the procedure described above, thus producing the 2l-acetate of 6-fiuoro-A -pregnatriene- 16a,17a,2l-triol-3,l1,20-trione. In another experiment the n-amyl alcohol was substituted by xylene, with the same final result.

PREPARATION XII A mixture of 2 g. of the 2l-acetate of 6ot-fluoro-A pregnene-16a,17u,21-triol-3,11,20-trione, obtained as described in Preparation XI, 1.6 g. of chloranil and 40 cc. of xylene was refluxed for 12 hours, cooled and diluted with ether. The solution was washed with water, 5% sodium carbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was purified by chromatography on neutral alumina to produce the 21-acetate of 6-flu0ro- A -pregnadiene-16a,17a,21-triol-3,11,2O-trione.

1 g. of the above compound was refluxed with 300 mg. of selenium dioxide, 50 cc. of anhydrous t-butanol and 0.2 cc. of pyridine for 70 hours under an atmosphere of nitrogen. The product was then worked up by the procedure described in the previous preparation. There was thus obtained the 21-acetate of 6-fiuoro-A -pregnatriene- 160:,17 u,21-triol-3,l1,20-trione, identical to the final compound obtained in the preceding preparation.

PREPARATION XIII A solution of 5 g. of 6-fluoro-3,20-bis-ethylenedioxy- A -pregnadien-21-ol-1l-one, prepared as described in 30 minutes.

Preparation V, in 150 cc. of anhydrous tetrahydrofuran was slowly added to a mechanically stirred suspension of 1.5 g. of lithium aluminum hydride in cc. of anhydrous tetrahydrofuran and the mixture was refluxed for The excess of anhydride was decomposed by the addition of a few drops of acetone and then 15 cc. of saturated aqueous sodium sulfate solution was added, followed by the addition of anhydrous sodium sulfate. The inorganic salts were removed by filtration and the solution was evaporated to dryness. Crystallization of the residue from acetone-ether yielded 6-fluoro- 3,20-bis-ethylenedioxy-A -pregnadiene-115,21-dio1.

In another experiment the above compound was obtained from the 2l-acetate of 6-fluoro-3,ZO-bis-ethylenedioxy A pregnadien-21-ol-1l-one, since the reaction with the hydride causes the simultaneous saponification of the acetoxy group at C-21.

The ketal groups of the above compound were then hydrolyzed following the method described in Preparation XI, to give 6rx-fiuoro-A -pregnadiene-11,8,21-dio1- 3,20-dione, which was in turn subjected to the treatment with osmium tetroxide, as described in that preparation, to produce Got-fluoro-16a-hydroxy-hydrocortisone.

There was then prepared the 21-acetate of 6a-fluoro- 16ot-hydroxy-hydrocortisone, and then the 2l-acetate of 6a-fluoro-16a-hydroxy-prednisolone, following exactly the method of acetylation and dehydrogenation as applied to 6a-fiuoro-16ot-hydroxy-cortisone.

PREPARATION XIV A culture of Streptomyces roseochromogenus Rutgers No. 3689 was prepared in an inclined agar medium containing 1% of glucose and 1% of yeast extract. 1 cc. of a suspension of this culture was then used to inoculate each one of a series of 250 cc. flasks containing 50 cc. of a sterilized aqueous medium of 2% peptone and 5% corn syrup; the mixtures were then incubated in a shaking machine at 28 C. under aeration for a period of 24-48 hours. There was thus obtained a vegetating growing culture of Streptomyces roseochromogenus which was used for the subsequent incubation of the steroid.

10 mg. of 6ot-fluoro-cortisone was added to each 50 cc. of the vegetating culture of Slreptomyces roseochromogenus, obtained as described above. The mixture was stirred for 48-72 hours with aeration and then extracted several times with methylene dichloride. The extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure.

The residue was purified by chromatography on silica, thus giving 6a-fiuoro-16a-hydroxy-cortisone, identical with that previously obtained.

PREPARATION XV The procedures of Preparation XI and XII are applied to 6a-methyl-cortisone as the starting material, and there are obtained the 2l-acetates of 6a-methyl-l6u-hydroxycortisone, Ga-methyl-16u-hydroxy-prednisone, 6a-methyl- A -pregnadienel6a,17a,21-triol-3,11,20-trione, and 6amethyl A pregnatriene-l6a,17u,21-triol-3,l1,20-trione, which can be used as starting materials in the process of the present invention.

PREPARATION XVI The procedure of Preparation X1 is applied to Got-methyl-cortisone as the starting material and there are obtained 6a-methyl A pregnene-l6a,17ot,2l-triol-3;11,20- trione, the 2'1-acetate of 6a-methyl-16a-hydroxy-prednisone, 6-methyl-A -pregnadiene-16a, 17a,21-trio1-3,1 1,20- trione, and 6-methyl-A -pregnatriene-16cc,17u,21-tri0l- 3,11,20-trione.

PREPARATION XVII The procedure of Preparation XI is applied to 2,8- nrethyl-cortisone as the starting material and there are '21 obtained ..2B-methyl-A pregnene-#16a,17a,21-triol 3,11,20- trione; the 21-acetate of Z-methyl-lGa-hydrOXy-predni- .sone, 'ZB-methyl-A fi-pregnadiene-16a,17a,2l-triol-3,11,20- trione, and 2-methyl-A -pregnatriene-16oz,17a,21-triol- 3,11,20-trione.

Example I By conventional methods (cf. for example Organic Syntheses, Coll. Vol. II, 165) there was prepared an ether solution of diazomethane'frorn N-nitroso-N-methylurea. To 100 cc. of anether solution of diazomethane prepared from '25 g. of nitrosomethylurea there was added a solution of 3.5 g. .of l6a-hydroXy-cortisone Zl-acetate in 200cc. of methylenechloride, followed by the addition of 1 cc. of an ether solution of fluoroboric acid containing 0.01 molar equivalents of reagent. The mixture was allowed to react at room temperature for 2 hours, then acidified with acetic acid and the solvent was evaporated under reduced pressure in a bath kept at a temperature below 40 C.; crystallization of the residue from acetone yielded 16a-methoxy-cortisone 21-acetate.

Example II In the preceding example, the fluoroboric acid was substituted by 0.01 molar equivalents of boron trifluoride etherate, with exactly the same result.

Example III Example I was repeated, however, acetone was used as the solvent for diazomethane instead of ether. The same results were obtained.

Example IV Example I was repeated with Qa-flHOIO-IGa-hYdIOXY- hydrocortisone 2l-propionate as the starting material. The final product obtained was 16a-methoxy-9a-fluorohydrocortisone 21-propionate.

Following the procedure of the preceding examples, using diazoethane or diazopropane as well as diazomethane, the final products listed in Table I below can be obtained from the indicated starting compounds:

Example XII A mixture of 1 g. of 16a-methoxy-cortisone 2l-acetate, obtained in accordance with the procedure described in Example I, with 20 cc. of a methanolic solution of sodium methoxide, prepared by dissolving 60 mg. of sodium metal in methanol, was stirred for 1 hour at C. and under an atmosphere of nitrogen. The mixture was then poured into 100 cc. of aqueous saturated sodium chloride solution containing 0.3 cc. of acetic acid and the precipitate was collected. by filtration, washed with water, dried and recrystallized from acetone-hexane. There was thus obtained the free 16u-methoxy-cortisone.

A mixture of 800 mg. of the above compound, 5 cc. of pyridine and 1 cc. of propionic anhydride was kept overnight at room temperature, poured into water, heated 22 for half an hour on the steam bath, cooled and the precipitate was collected by filtration. It was washed with water, dried and recrystallized 'from acetone-hexane, thus afiording 16a-methoXy-cortisone21-propionate.

Example XIII By following the methods of the preceding examples, all of the 16a-hydroxy-hormones esterified at C-2l which may serve as starting compounds in our method, were converted into the corresponding 21-esters of the respective 16a-alkoxy-cortical hormones; the ester group was hydrolyzed and the hydroxyl group at C21 was eventually reesterified.

Thus we prepared among other compounds those listed in Table II given hereinafter from the starting materials listed therein:

TABLE II Exlalmple Starting Ester Final Product XIII lfinz-ethoxy-cortisone 21- lfia-ethoxy-cortisonc.

acetate (Ex. V).

XIV lfia-ethoxy-cortisone 21- lfia-ethoxy-cortisone 21- acetate. propionate.

XV l6a-methoxy-hydrocortisone 16a-meth0xy-hydrocortisone.

21-acctate (Ex. IX).

XVI 1fiwethoxy-hydrocortisone lfia-ethoxy-hydrocortisone.

21-acetate (Ex. X).

XVII.-." lfia-propoxy hydrocortisone 1fia-propoxy-hydrocortisone.

21acetate (Ex. XI).

XVIII. Ida-methoxy-hydrocortisone 1fia-methoxy-hydrocortlsone 21-acetate (Ex. IX). 2l-clopentylpropionate.

XIX 16a-ethoxy-hydrocortisone 1fia-ethoxy-hydrocortisone (Ex. X). 21-cy1copentylpropionate.

XX 1fi-apropoxy-hydrocortisone lea-propoxy-hydrocortisone (Ex. XI). 21 cyelopentylpropionatc.

XXI 16a-ethoxy6a,9a-difluoro- 16-ethoxy-6a,9a-d1fiuoroprednisone 21-acetate prednisone. (from the lda-hydroxy compound by the process described in Ex. I).

XXII 0 16a-ethoxy-6a,Qwdifiuoroprednisone 21-butyrate.

XXIII. G-mBthYI-IGa-GthOXY-Qa- 6methyl-16a-ethoxy-9afluoro-A -pregnatrienefluoro-A 4. -pregnartriene- 115,170, 21triol-3,21-dione 11B,17a,2l-triol3,20-di0ne. 21-acetate (from the hydroxy compound by the process described in Ex. 1).

We claim: 1. A compound having the formula CHQOR Y ---Alkoxy wherein R is selected from the group consisting of hydrogen and hydrocarbon acyl radicals having maximally 12 carbon atoms; X is selected from the group consisting of hydrogen, methyl and ethyl, X is selected from the group consisting of hydrogen, methyl, fluorine, chlorine and bromine, X" is selected from the group consisting of hydrogen, fluorine, chlorine, and bromine, Y is selected from the group consisting of :0 and and Z is selected from the group consisting of a single bond between 0-1 and C-2 and a double bond between C-l and C-2.

2. l6oc-lOW6I' alkoxy-6-halo-6-dehydro-cortisone.

3. 16x-lower alkoxy-6-halo-G-dehydro-hydrocortisone.

4. 16oL-lOWGI' alkoxy-6-halo-6-dehydro-prednisone.

5. 160c-1OW6I' alkoxy-6-halo-G-dehydro-prednisolone.

6. 16oc-1OWC1' alkoxy-6-methyl-6-dehydro-cortisone. 

1. A COMPOUND HAVING THE FORMULA 